If you have a long scenario ahead of you, try to
seek out cash cow routes that can help keep you in the
black. Look for places to create miniroutes between two
industries that can feed off of each other; set up two
small stations and buy yourself the cheapest, most reliable
engine possible (speed doesn't really matter on such a
short route). Afterward, you should find yourself with a
solid and steady flow of income as you work on your grander
visions. Tip:

If you use the "auto" track-laying feature, be sure
to turn the grid on (press the G key) and build in small
sections to give yourself the most control over slopes
and hills. Tip:

Once you get into high-tech locomotives such as the
TGV and the Brenner, you need to evaluate maintenance,
fuel, and start-up costs for these massive brutes.
It's one thing to fork over $200,000 for a new engine in
RTII, but now you can spend more than a million bucks on
one of these new beauties. Make sure it'll pay off for you
down the road! Tip:

In the Metra scenarios, build more small stations instead
of fewer large ones. You still serve the same population, but
the shorter distance between stops means a faster flowing income
stream (and less real estate you have to bulldoze).